title: Mutation of a diacidic motif in SIV-PBj Nef impairs T-cell activation and enteropathic disease.
abstract: BACKGROUND
  The non-pathogenic course of SIV infection in its natural host is characterized by robust viral replication in the absence of chronic immune activation and T cell proliferation. In contrast, acutely lethal enteropathic SIVsmm strain PBj induces a strong immune activation and causes a severe acute and lethal disease in pig-tailed macaques after cross-species transmission. One important pathogenicity factor of the PBj virus is the PBj-Nef protein, which contains a conserved diacidic motif and, unusually, an immunoreceptor tyrosine-based activation motif (ITAM).
  
  
  RESULTS
  Mutation of the diacidic motif in the Nef protein of the SIVsmmPBj abolishes the acute phenotype of this virus. In vitro, wild-type and mutant PBj (PBj-Nef202/203GG) viruses replicated to similar levels in macaque PBMCs, but PBj-Nef202/203GG no longer triggers ERK mitogen-activated protein (MAP) kinase pathway including an alteration of a Nef-associated Raf-1/ERK-2 multiprotein signaling complex. Moreover, stimulation of IL-2 and down-modulation of CD4 and CD28 were impaired in the mutant virus. Pig-tailed macaques infected with PBj-Nef202/203GG did not show enteropathic complications and lethality as observed with wild-type PBj virus, despite efficient replication of both viruses in vivo. Furthermore, PBj-Nef202/203GG infected animals revealed reduced T-cell activation in periphery lymphoid organs and no detectable induction of IL-2 and IL-6.
  
  
  CONCLUSIONS
  In sum, we report here that mutation of the diacidic motif in the PBj-Nef protein abolishes disease progression in pig-tailed macaques despite efficient replication. These data suggest that alterations in the ability of a lentivirus to promote T cell activation and proliferation can have a dramatic impact on its pathogenic potential.
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institut, Langen, Germany. floeg@pei.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Tschulena
authors.forename: Ralf
authors.initials: R
authors.lastname: Sanzenbacher
authors.forename: Michael D
authors.initials: MD
authors.lastname: Mühlebach
authors.forename: André
authors.initials: A
authors.lastname: Berger
authors.forename: Jan
authors.initials: J
authors.lastname: Münch
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.forename: Roland
authors.initials: R
authors.lastname: Plesker
authors.forename: Cheick
authors.initials: C
authors.lastname: Coulibaly
authors.forename: Sylvia
authors.initials: S
authors.lastname: Panitz
authors.forename: Steffen
authors.initials: S
authors.lastname: Prüfer
authors.forename: Heide
authors.initials: H
authors.lastname: Muckenfuss
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamdorf
authors.forename: Matthias
authors.initials: M
authors.lastname: Schweizer
authors.forename: Klaus
authors.initials: K
authors.lastname: Cichutek
authors.forename: Egbert
authors.initials: E
authors.lastname: Flory
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002478:Cells, Cultured; D003106:Colon / Q000473:pathology* / Q000821:virology; D015693:Gene Products, nef / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D008231:Lymphopenia / Q000821:virology; D008254:Macaca nemestrina; D008992:Monkey Diseases / Q000276:immunology / Q000473:pathology / Q000821:virology; D009154:Mutation; D010641:Phenotype; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D013601:T-Lymphocytes / Q000276:immunology*; D014766:Viremia / Q000821:virology; D014779:Virus Replication
chemical_list: D015693:Gene Products, nef